Proteins are fundamental components within every living cell, acting as the primary building blocks and carrying out countless functions. These complex molecules must fold into precise three-dimensional shapes to perform their specific tasks effectively. However, the cellular environment can be challenging, and proteins often require assistance to achieve and maintain their correct structures. This is where specialized helper proteins, known as molecular chaperones, become important, guiding other proteins through their folding pathways and safeguarding their integrity.
What is HSP90?
HSP90, or Heat Shock Protein 90, is a family of molecular chaperones found across diverse organisms, from bacteria to humans. It is one of the most abundant proteins in cells, making up approximately 1-2% of total cellular protein in unstressed conditions, increasing to 4-6% when cells are under stress, such as elevated temperatures. HSP90’s primary role involves assisting a specific group of proteins, termed “client proteins,” in achieving their correct three-dimensional conformation and maintaining their stability. This chaperoning activity is important during cellular stress responses, preventing protein misfolding or aggregation under unfavorable conditions.
HSP90 acts as a quality control mechanism within the cell, ensuring its client proteins remain functional and properly regulated. Many of these client proteins are involved in important cellular processes like cell growth, survival, and signaling pathways. By supporting the correct folding and stability of these diverse clients, HSP90 plays a broad role in maintaining overall cellular balance, known as homeostasis. Its widespread presence and multifaceted functions highlight its importance in cellular biology.
The Molecular Weight of HSP90
The molecular weight of a single HSP90 unit, known as a monomer, is approximately 90 kilodaltons (kDa). For example, human HSP90 alpha (Hsp90α) is composed of 733 amino acids and has a molecular weight of about 86 kDa.
HSP90 functions as a dimer. This dimerization results in a combined molecular weight for the active HSP90 complex of approximately 180 kDa. Variations in molecular weight can exist depending on the organism or specific isoform of HSP90. For instance, the bacterial homolog of HSP90, HtpG, has a molecular weight of about 71.424 kDa.
How HSP90’s Structure Relates to Its Function
HSP90’s large size and dimeric structure are important for its ability to chaperone a wide array of client proteins. Each HSP90 monomer consists of three main structural domains: an N-terminal domain (NTD), a middle domain (MD), and a C-terminal domain (CTD). The N-terminal domain is responsible for binding ATP, a molecule that provides the energy for HSP90’s activity, while the middle domain is involved in binding to client proteins. The C-terminal domain facilitates the dimerization of the two HSP90 monomers.
The dimeric arrangement allows HSP90 to act like a “molecular clamp” that can open and close, driven by the binding and hydrolysis of ATP. When ATP binds to the N-terminal domains, it induces conformational changes, causing the dimer to shift from an open, more relaxed state to a closed, more compact state. This dynamic shape-shifting is important for HSP90 to capture, process, and release its client proteins effectively. The ability to undergo these structural rearrangements enables HSP90 to accommodate and assist a diverse range of client proteins, many of which are signal transducing molecules like protein kinases and steroid hormone receptors.
HSP90’s Importance in Cellular Health and Disease
HSP90’s widespread involvement in maintaining the stability and function of numerous client proteins directly links it to overall cellular health. Its role in diverse cellular processes such as cell cycle control, cell survival, and various signaling pathways means that any dysfunction in HSP90 can have broad implications. In healthy cells, HSP90 helps to prevent the aggregation of misfolded proteins and supports the proper functioning of newly synthesized proteins. This contribution to protein quality control is an important aspect of cellular well-being.
Given its extensive network of client proteins, HSP90 has emerged as a significant factor in the progression of several diseases. In cancer, for example, HSP90 often stabilizes oncogenic proteins—proteins that promote uncontrolled cell growth and survival. By protecting these abnormal proteins from degradation, HSP90 can contribute to the malignant transformation of cells and tumor progression. Conversely, in neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases, where protein misfolding and aggregation are hallmarks, HSP90’s activity can be altered, potentially contributing to the accumulation of toxic protein aggregates. Consequently, HSP90 is being explored as a therapeutic target, with inhibitors being developed to disrupt its function in diseases like cancer, aiming to destabilize and degrade the problematic client proteins it supports.